Method for preparing aryl crown ether compound by one-pot method

Abstract

The invention discloses a method for preparing an aryl crown ether compound by a one-pot method, which comprises the following steps: reacting polyethylene glycol with sulfuryl fluoride or chlorofluorosulfonyl in an organic solvent under the action of alkali to obtain polyethylene glycol difluorosulfonyl ester; the aryl crown ether compound is obtained by reacting a dihydroxy aryl compound with polyethylene glycol difluorosulfonyl ester in an organic solvent under the action of a catalyst and alkali. According to the invention, a common economic protection reagent, namely sulfuryl fluoride or chlorofluorosulfonyl, is used for reaction, and various aryl crown ether compounds can be prepared by a one-pot method. The product obtained by the synthesis method has the advantages of simplicity in operation, low cost, high yield and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for preparing an aryl crown ether compound by a one-pot process. Background Art

[0002] Aryl crown ethers are a special class of crown ether compounds, which have one or more cyclic ether units and an aryl substituent introduced at a certain position of the ring. These compounds are widely used in many fields, including chemical sensing, ion selectivity, drug delivery, separation technology, etc. due to their unique molecular structure and excellent selectivity. At the same time, aryl crown ethers also show important application potential in supramolecular chemistry and materials science.

[0003] Although aryl crown ethers have broad application prospects, their synthesis methods have many shortcomings. The traditional synthesis route usually includes multiple steps, such as di-p-toluenesulfonate esterification reaction, aryl functionalization, cyclization reaction and post-treatment, which not only increases the complexity of the synthesis but also reduces the yield. For example, the commonly used aryl ether synthesis methods include Friedel-Crafts reaction, iodination reaction, and other coupling reactions, which often require high temperature and long reaction time, and may generate a large amount of by-products.

[0004] In particular, the use of p-toluenesulfonyl chloride, although widely used to prepare di-p-toluenesulfonated polyglycol chains, has disadvantages such as low atom utilization, complex reaction steps, selectivity and yield issues, and harsh reaction conditions that limit its practical application. The treatment of waste and by-products generated during the synthesis process also poses challenges to environmental protection. Summary of the invention

[0005] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

[0006] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0007] One of the objects of the present invention is to provide a one-pot method for preparing an aryl crown ether compound, using polyglycol difluorosulfonyl ester to prepare the aryl crown ether, thereby improving the yield and avoiding the separation cost caused by column chromatography.

[0008] In order to solve the above technical problems, the present invention provides the following technical solution: a one-pot method for preparing an aryl crown ether compound, comprising:

[0009] Polyethylene glycol reacts with sulfuryl fluoride or chlorofluorosulfonyl in an organic solvent A under the action of a base A to obtain a polyethylene glycol difluorosulfonyl ester as shown in formula I;

[0010]

[0011] Wherein, n=1 to 5;

[0012] A dihydroxy aromatic compound reacts with a polyglycol difluorosulfonyl ester shown in formula I in an organic solvent B under the action of a catalyst and a base B to obtain an aromatic crown ether compound;

[0013] The dihydroxy aromatic compound is selected from one of the following compounds:

[0014]

[0015] The aryl crown ether compound is one of the following compounds:

[0016]

[0017] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 It is one of hydrogen, aliphatic group, halogen, alkoxy group, nitro group, cyano group and aryl group, and n=0-6.

[0018] As a preferred embodiment of the one-pot method for preparing an aryl crown ether compound of the present invention, the base A is any one or more of an inorganic base and / or an organic base; including one of triethylamine, cesium carbonate, and diisopropylethylamine;

[0019] The polyethylene glycol is any one of diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, and hexaethylene glycol;

[0020] The molar ratio of the polyglycol to the base A is 1:1-20.

[0021] As a preferred embodiment of the method for preparing an aromatic crown ether compound by a one-pot process of the present invention, the organic solvent A is selected from one or more of acetonitrile, dichloromethane, ethyl acetate, benzene, toluene, acetone, 1,4-dioxane, ether, tetrahydrofuran, methyltetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether and chloroform.

[0022] As a preferred embodiment of the one-pot method for preparing an aryl crown ether compound of the present invention, the sulfuryl fluoride or chlorofluorosulfonyl is a gas, and sulfuryl fluoride or chlorofluorosulfonyl gas is introduced into a mixture of polyglycol, base A, and organic solvent A for reaction, and the introduction of sulfuryl fluoride or chlorofluorosulfonyl gas is stopped when the content of glycol in the system is less than 0.3%.

[0023] As a preferred embodiment of the one-pot method for preparing an aryl crown ether compound of the present invention, the molar ratio of the dihydroxy aromatic compound to the polyglycol difluorosulfonyl ester is 1:0.2-20.

[0024] As a preferred embodiment of the one-pot method for preparing an aryl crown ether compound of the present invention, the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylcyanamide sulfate and tetrabutylammonium chloride;

[0025] The added amount of the catalyst is 1 to 50 mol% of the dihydroxy aromatic compound.

[0026] As a preferred embodiment of the one-pot method for preparing an aryl crown ether compound of the present invention, the base B is any one or more of an inorganic base and / or an organic base, including one of sodium hydroxide, sodium hydrogen sulfide, and potassium carbonate;

[0027] The added amount of the base B is 100 to 2000 mol % of the polyglycol difluorosulfonyl ester.

[0028] As a preferred embodiment of the method for preparing an aromatic crown ether compound by a one-pot process of the present invention, the organic solvent B is selected from one or more of acetonitrile, dichloromethane, ethyl acetate, benzene, toluene, acetone, 1,4-dioxane, ether, tetrahydrofuran, methyltetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether and chloroform.

[0029] As a preferred embodiment of the one-pot method for preparing an aryl crown ether compound of the present invention, the reaction temperature is -10 to 100° C. and the reaction time is 1 to 24 hours.

[0030] As a preferred embodiment of the method for preparing an aryl crown ether compound by a one-pot process of the present invention, the method further comprises the step of purifying the reaction product aryl crown ether compound.

[0031] As a preferred embodiment of the one-pot method for preparing an aryl crown ether compound of the present invention, the dihydroxy aromatic compound may be a chiral dihydroxy aromatic compound, which may be racemic or chiral.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The present invention effectively uses sulfuryl fluoride or chlorofluorosulfonyl to replace p-toluenesulfonyl chloride, and sulfuryl fluoride or chlorofluorosulfonyl itself is low in price, saving costs. The present invention uses polyglycol difluorosulfonyl ester to prepare aryl crown ether, improves the yield, avoids the separation cost caused by column chromatography, reduces the overall process production cost, and improves market competitiveness. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative labor. Among them:

[0035] Figure 1 is the NMR spectrum of the aryl crown ether compound produced in Example 2 of the present invention;

[0036] Figure 2 This is the NMR spectrum of the aryl crown ether compound produced in Example 3 of the present invention. DETAILED DESCRIPTION

[0037] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0038] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0039] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0040] Unless otherwise specified, the raw materials used in the examples were purchased commercially.

[0041] Example 1

[0042] (1) Tetraethylene glycol (6.47 g, 33.3 mmol) and triethylamine (9.26 mL, 66.6 mmol) were added to a 250 mL round-bottom flask containing 50 mL of dichloromethane. The temperature was lowered to 0°C, sulfuryl fluoride was introduced into the reaction solution and stirred at room temperature for 2 hours. When the content of glycol in the system was less than 0.3%, the introduction of sulfuryl fluoride gas was stopped. After the reaction was completed, nitrogen was introduced into the reaction system to purge the residual sulfuryl fluoride gas in the system to obtain a tetraethylene glycol difluorosulfonyl ester solution.

[0043] The reaction formula is:

[0044]

[0045] (2) Under nitrogen protection, sodium hydroxide (40.0 mg, 1.0 mmol) and tetrabutylammonium bromide (8.1 mg) were added to catechol (55.0 mg, 0.5 mmol) in 10 mL of dichloromethane solution and reacted at 0°C for 30 min. Subsequently, tetraethylene glycol difluorosulfonyl ester solution (1.0 mmol) was added, and the reaction solution was refluxed for 3 h before the reaction was completed. The product was extracted three times with dichloromethane, washed three times with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The filtrate was evaporated to remove the organic solvent to obtain the product as a white solid (125 mg, 93%). 1H NMR (500 MHz, Chloroform-d) 6.92–6.85 (m, 4H), 4.18–4.11 (m, 4H), 3.94–3.89 (m, 4H), 3.74–3.79 (m, 8H).

[0046] The reaction formula is:

[0047]

[0048] Example 2

[0049] (1) Add pentaethylene glycol (7.93 g, 33.3 mmol) and triethylamine (9.26 mL, 66.6 mmol) into a 250 mL round-bottom flask containing 50 mL of dichloromethane. Cool to 0°C, pass sulfuryl fluoride into the reaction solution and stir at room temperature for 2 hours. When the content of glycol in the system is less than 0.3%, stop passing sulfuryl fluoride gas. After the reaction is completed, pass nitrogen into the reaction system to purge the residual sulfuryl fluoride gas in the system to obtain pentaethylene glycol difluorosulfonyl ester solution.

[0050] The reaction formula is:

[0051]

[0052] (2) Under nitrogen protection, sodium hydride (40.0 mg, 1.0 mmol) and tetrabutylammonium chloride (7.0 mg) were added to S-1,1'-bi-2-naphthol (144.6 mg, 0.5 mmol) in 10 mL of dichloromethane solution and reacted at 0°C for 30 min. Subsequently, pentaethylene glycol difluorosulfonyl ester solution (1.0 mmol) was added, and the reaction solution was refluxed for 3 h before the reaction was completed. The product was extracted three times with dichloromethane, washed three times with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After the filtrate was evaporated to remove the organic solvent, the product was obtained as a colorless oil (144 mg, 96%). 1HNMR (500MHz, Chloroform-d) δ7.92 (d, J = 9.0Hz, 2H), 7.84 (d, J = 8.2Hz, 2H), 7.46 (d, J = 9.0Hz, 2H), 7.30 (ddd, J = 8.1, 6.5, 1.2Hz, 2H), 7.19 (ddd, J = 8.1, 6.6, 1.3Hz, 2H), 7.13 (d, J = 8.5Hz, 2H), 4.19 (ddd, J = 10.9, 7.2, 4.1Hz, 2H), 4.02 (dt, J = 10.5, 4.4Hz, 2H), 3.64–3.55 (m, 6H), 3.52–3.46 (m, 6H), 3.37 (t, J = 4.4Hz, 4H). Figure 1 shown.

[0053] The reaction formula is:

[0054]

[0055] Example 3

[0056] (1) Prepare pentaethylene glycol difluorosulfonyl ester solution in the same manner as in Example 2.

[0057] (2) Under nitrogen protection, potassium carbonate (138.2 mg, 1.0 mmol) and tetrabutylammonium hydrogen sulfate (8.5 mg) were added to (R)-spirocyclodiphenol (126.2 mg, 0.5 mmol) in 10 mL of acetonitrile solution and reacted at 0°C for 30 min. Subsequently, pentaethylene glycol difluorosulfonyl ester solution (1.0 mmol) was added, and the reaction solution was heated to 60°C. The reaction was completed after 5 h. The product was extracted three times with dichloromethane, washed three times with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After the filtrate was evaporated to remove the organic solvent, the product was obtained as a colorless oil (225 mg, 99%). 1HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.7Hz,2H),6.83(dd,J=7.5,1.0Hz,2 H),6.67(d,J=8.0Hz,2H),4.05(ddd,J=10.4,6.8,4.8Hz,2H),3.88(dt,J=10.2,4 .8Hz,2H),3.66–3.60(m,2H),3.56–3.45(m,8H),3.33–3.20(m,6H),2.99(dd,J=8 .9, 4.9Hz, 4H), 2.31 (dt, J = 12.5, 9.3Hz, 2H), 2.15 (ddd, J = 12.5, 6.2, 4.6Hz, 2H). NMR spectra Figure 2 shown.

[0058] The reaction formula is:

[0059]

[0060] Example 4

[0061] (1) Prepare tetraethylene glycol difluorosulfonyl ester solution in the same manner as in Example 1.

[0062] (2) Under nitrogen protection, sodium hydrogen sulfide (40 mg, 1.0 mmol) and tetrabutylammonium hydrogen sulfate (8.5 mg) were added to 2,2'-biphenol (126.2 mg, 0.5 mmol) in 10 mL of methyltetrahydrofuran solution and reacted at 0°C for 30 min. Subsequently, tetraethylene glycol difluorosulfonyl ester solution (1.0 mmol) was added, and the reaction solution was heated to 60°C. The reaction was completed after 5 h. The product was extracted three times with dichloromethane, washed three times with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After the filtrate was evaporated to remove the organic solvent, the product was obtained as a white solid (169 mg, 98%). 1H NMR (500MHz, Chloroform-d) δ7.23 (m, 2H), 7.15 (dd, 2H, J = 12.3Hz, 3.0Hz), 6.95 (m, 4H), 4.21 (m, 2H), 3.95 (m, 2H), 4.66 (m, 12H).

[0063] The reaction formula is:

[0064]

[0065] Example 5

[0066] (1) Prepare tetraethylene glycol difluorosulfonyl ester solution in the same manner as in Example 1.

[0067] (2) Under nitrogen protection, sodium hydrogen sulfide (40.0 mg, 1.0 mmol) and tetrabutylammonium chloride (7.0 mg) were added to 1,8-dihydroxynaphthalene (80.1 mg, 0.5 mmol) in 10 mL of dichloroethane solution and reacted at 0°C for 30 min. Subsequently, tetraethylene glycol difluorosulfonyl ester solution (1.0 mmol) was added, and the reaction solution was refluxed for 3 h before the reaction was completed. The product was extracted three times with dichloromethane, washed three times with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The filtrate was evaporated to remove the organic solvent to obtain the product as a white solid (151 mg, 95%). 1H NMR (500 MHz, Chloroform-d) δ7.45–7.10 (m, 4H), 6.91–6.59 (m, 4H), 4.32–3.38 (m, 16H).

[0068] The reaction formula is:

[0069]

[0070] Example 6

[0071] (1) Prepare tetraethylene glycol difluorosulfonyl ester solution in the same manner as in Example 1.

[0072] (2) Under nitrogen protection, sodium hydrogen hydride (40.0 mg, 1.0 mmol) and tetrabutylammonium chloride (7.0 mg) were added to (S)-6,6'-dibromobinaphthol (222.1 mg, 0.5 mmol) in 10 mL of acetonitrile solution and reacted at 0°C for 30 min. Subsequently, tetraethylene glycol difluorosulfonyl ester solution (1.0 mmol) was added, and the reaction solution was refluxed for 3 h before the reaction was completed. The product was extracted three times with dichloromethane, washed three times with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After the filtrate was evaporated to remove the organic solvent, the product was obtained as a white solid (310 mg, 96%). 1H NMR(500MHz,Chloroform-d)δ7.99(d,J=1.9Hz,2H),7.82(d,J=9.2Hz,2H),7.47(d,J=9.0Hz,2H),7.25(dd,J=15.0, 2.5Hz, 2H), 6.96 (d, J = 15.0Hz, 2H), 4.14–4.25 (m, 4H), 3.97–4.07 (m, 4H), 3.43–3.67 (m, 8H), 3.39 (t, J = 6.7Hz, 4H).

[0073] The reaction formula is:

[0074]

[0075] Example 7

[0076] (1) Triethylene glycol (5.00 g, 33.3 mmol) and triethylamine (9.26 mL, 66.6 mmol) were added to a 250 mL round-bottom flask containing 50 mL of dichloromethane. The temperature was lowered to 0°C, sulfuryl fluoride was introduced into the reaction solution and stirred at room temperature for 2 hours. When the content of glycol in the system was less than 0.3%, the introduction of sulfuryl fluoride gas was stopped. After the reaction was completed, nitrogen was introduced into the reaction system to purge the residual sulfuryl fluoride gas in the system to obtain a triethylene glycol difluorosulfonyl ester solution.

[0077]

[0078] (2) Under nitrogen protection, potassium hydroxide (56.1 mg, 1.0 mmol) and tetrabutylammonium hydrogen sulfate (8.5 mg) were added to dimethylcatechol (69.1 mg, 0.5 mmol) in 10 mL of tetrahydrofuran solution and reacted at 0°C for 30 min. Subsequently, triethylene glycol difluorosulfonyl ester solution (1.0 mmol) was added, and the reaction solution was refluxed for 3 h before the reaction was completed. The product was extracted three times with dichloromethane, washed three times with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The filtrate was evaporated to remove the organic solvent to obtain the product as a white solid (123 mg, 97%). 1H NMR (500 MHz, Chloroform-d) δ 6.78 (s, 2H), 4.17–4.13 (m, 4H), 3.86–3.78 (m, 8H), 2.19 (s, 6H).

[0079] The reaction formula is:

[0080]

[0081] Example 8

[0082] Example 8 is basically the same as Example 1, except that the organic solvent in step (2) is different, as shown in Table 1 below:

[0083] Table 1

[0084] Solvents Yield (%) THF 93 MeCN 91 DCE 95 2-MeTHF 92 DCM 96 DMSO 55 DMF 72

[0085] It can be seen from Table 1 that under the same reaction conditions, the target compound can be obtained in different organic solvents, among which the yields in the organic solvents THF, MeCN, DCE, 2-MeTHF and DCM are better.

[0086] Example 9

[0087] Example 9 is basically the same as Example 1, except that the catalyst in step (2) is different, as shown in Table 2 below:

[0088] Table 2

[0089]

[0090]

[0091] It can be seen from Table 2 that under the same reaction conditions, the catalytic efficiencies and yields of different catalysts are similar.

[0092] The present invention uses sulfuryl fluoride or chlorofluorosulfonyl, which is a commonly used and economical protective reagent, to react, and a variety of aryl crown ether compounds can be prepared by a one-pot method. The product obtained by the synthesis method has the advantages of simple operation, low cost, high yield, etc.

[0093] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A one-pot method for preparing an aryl crown ether compound, characterized in that: include, Polyethylene glycol reacts with sulfuryl fluoride or chlorofluorosulfonyl in an organic solvent A under the action of a base A to obtain a polyethylene glycol difluorosulfonyl ester as shown in formula I; Wherein, n=1 to 5; A dihydroxy aromatic compound reacts with a polyglycol difluorosulfonyl ester shown in formula I in an organic solvent B under the action of a catalyst and a base B to obtain an aromatic crown ether compound; The dihydroxy aromatic compound is selected from one of the following compounds: The aryl crown ether compound is one of the following compounds: Among them, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are one of hydrogen, aliphatic group, halogen, alkoxy group, nitro group, cyano group, and aromatic group, and n=0-6.

2. The method for preparing an aryl crown ether compound by a one-pot process as claimed in claim 1, characterized in that: The base A is any one or more of an inorganic base and / or an organic base; including one of triethylamine, cesium carbonate, and diisopropylethylamine; The polyethylene glycol is any one of diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, and hexaethylene glycol; The molar ratio of the polyglycol to the base A is 1:1-20.

3. The one-pot method for preparing an aryl crown ether compound according to claim 1 or 2, characterized in that: The organic solvent A is selected from one or more of acetonitrile, dichloromethane, ethyl acetate, benzene, toluene, acetone, 1,4-dioxane, ether, tetrahydrofuran, methyltetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether and chloroform.

4. The one-pot method for preparing an aryl crown ether compound according to claim 3, characterized in that: The sulfuryl fluoride or chlorofluorosulfonyl is a gas, and sulfuryl fluoride or chlorofluorosulfonyl gas is introduced into a mixture of glycol, base A, and organic solvent A for reaction. When the glycol content in the system is less than 0.3%, the introduction of sulfuryl fluoride or chlorofluorosulfonyl gas is stopped.

5. The one-pot method for preparing an aryl crown ether compound according to any one of claims 1, 2 and 4, characterized in that: The molar ratio of the dihydroxy aromatic compound to the polyglycol difluorosulfonyl ester is 1:0.2-20.

6. The one-pot method for preparing an aryl crown ether compound according to claim 5, characterized in that: The catalyst is one of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylcyanamide sulfate, and tetrabutylammonium chloride; The added amount of the catalyst is 1 to 50 mol% of the dihydroxy aromatic compound.

7. The one-pot method for preparing an aryl crown ether compound according to any one of claims 1, 2, 4, and 6, characterized in that: The base B is any one or more of an inorganic base and / or an organic base, including one of sodium hydroxide, sodium hydrogen sulfide, and potassium carbonate; The added amount of the base B is 100 to 2000 mol % of the polyglycol difluorosulfonyl ester.

8. The one-pot method for preparing an aryl crown ether compound according to claim 7, characterized in that: The organic solvent B is selected from one or more of acetonitrile, dichloromethane, ethyl acetate, benzene, toluene, acetone, 1,4-dioxane, ether, tetrahydrofuran, methyltetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether and chloroform.

9. The one-pot method for preparing an aryl crown ether compound according to any one of claims 1, 2, 4, 6, and 8, characterized in that: The reaction temperature is -10 to 100°C and the reaction time is 1 to 24 hours.

10. The one-pot method for preparing an aryl crown ether compound according to claim 9, characterized in that: The method also includes a step of purifying the reaction product, the aryl crown ether compound.

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